Irisin Mediates Effects on Bone via αV Integrin Receptors

Exercise is crucial to prevent obesity, diabetes, fatty liver disease, and osteoporosis. These beneficial effects are partially mediated by myokines, hormone‐like molecules produced by skeletal muscle. Irisin is a myokine which is a cleaved product from fibronectin type III domain‐containing protein 5 (FNDC5) and is shed into the intracellular milieu and blood circulation to reach other organs. Particularly irisin has been shown to have beneficial effects in adipose tissues, brain, and bone. However, the skeletal response to exercise is less clear and the receptor for irisin has not been identified. Here we show that irisin binds to proteins of the αV class of integrins and biophysical studies identify interacting surfaces between irisin and αV/β5 integrin. Irisin increases both osteocytic survival and production of sclerostin, a local modulator of bone remodeling. Chemical inhibition of the αV integrins blocks signaling and function by irisin in osteocytes and fat cells. In vivo , injection of recombinant irisin protein increases the expression of sclerostin in osteocyte‐enriched bone as well as the levels of plasma sclerostin, and chemical inhibition of the αV integrins blocks the irisin‐induced effects. Genetic ablation of FNDC5/irisin completely blocks osteocytic osteolysis and bone resorption induced by ovariectomy, preventing bone loss and supporting an important role for irisin in skeletal remodeling. The identification of the irisin receptor and its roles in bone biology should greatly facilitate our understanding of irisin's function in exercise and human health. Support or Funding Information Hyeonwoo (Chad) Kim was supported by a cardiovascular T32 grant (5T32HL007374‐38). Bruce M. Spiegelman was supported by NIH grants (4 R01DK54477‐19, DK61502, B.M.S.) and the JPB Foundation (629803). Lynda F. Bonewald was supported by NIH grant (PO1AG039335). Clifford J. Rosen was supported by NIH grant (NIDDK RC2 092759). This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .